Netrins are a family of molecules that were first shown to be involved in axon guidance in brain tissue (Guthrie, S. 1997. Curr. Biol. 7:R6-R9; Livesey, F. J. 1999. Cell. Mol. Life. Sci. 56:62-68). Netrins act as either attractants or repellants depending on the type of netrin receptors expressed on growth cones (Koch, M. et al. 2000. J. Cell Biol. 151:221-234). Several netrins have been identified and named netrin-1, netrin-2, netrin-3 and netrin-4. Only netrin-1, netrin-3 and netrin-4 have been linked to human physiology and development. Netrins 1 through 3 are structurally-related to the short arms of laminin-gamma chains, while netrin-4, also known as beta-netrin, has been shown to related to the laminin-beta chains (Koch, M. et al. 2000. J. Cell Biol. 151:221-234).
Studies have shown that netrin-4 is expressed in various areas of the nervous system and that this protein plays a role in neurite outgrowth. Recent studies have shown that netrin-4 is widely expressed in human and mouse tissues, having been detected in spleen, prostate, ovary, heart, kidney, pancreas, mammary gland, and uterus (Koch, M. et al. 2000. J. Cell Biol. 151:221-234). Other physiological roles have been discussed in association with netrin-4 including promotion of neuronal plasticity in adult brain (Zhang, C. et al. 2004. Brain Res. Mol. Brain. Res. 130:68-80), lung development (Liu, Y. et al. 2004. Curr. Biol. 14:897-905), and axon growth and migration (Qin, S. et al. 2007. Mol. Cell. Neurosci. 34:243-250).
Additionally, U.S. Patent Application 2003/0207347 describes a role for netrin-4 proteins or polypeptides in the development and/or regeneration of the nervous system. Netrin-4 activities disclosed include the ability to modulate neurite outgrowth, guidance, and/or stability; the ability to modulate development of the central nervous system, including development of the spinal cord, development of the optic system, and development of the olfactory system; the ability to modulate development of areas of the brain; the ability to modulate angiogenesis, including inhibition of angiogenesis in tumors; the ability to modulate proliferative disorders such as cancer; the ability to modulate development of the kidney, including morphogenesis of tubules and glomeruli; the ability to modulate the maturation of ovarian follicles; and the ability to modulate muscular development and/or innervation, especially smooth muscle. A related application, U.S. Patent Application 2004/0248178, further describes specific roles for netrin-4 and variants of netrin-4 in modulating kidney, ovary, heart, or muscle development.
Another U.S. Patent Application (2006/0019896) discloses uses of netrin-4 for the promotion of angiogenesis, promotion of migration of endothelial cells and smooth muscle cells, promotion of stem cell proliferation, decreasing inflammation, inhibiting tumor growth, preventing and treating adhesions, and treatment of neuropathy. U.S. Patent Application 2006/0025335 discloses use of netrin-4 to modulate inflammatory cell movement and then the treatment of patients with adverse immune responses. The application links netrin-4-related alterations in inflammatory cell movement to treatment of dozens of immune system diseases. Finally, WO/2006/054000 describes mutated netrin-4 molecules and their use as therapeutics to prevent and treat cancer.
The specific cellular events linked to netrin-4 and its potential effects in humans are under investigation. It has now been found that netrin-4 acts as a signaling molecule secreted from endothelial cells and is capable of inducing pancreatic and liver cell differentiation in embryonic cells, thereby having the ability to alter pancreatic and liver cell function.